The Taxanes: Dosing and Scheduling Considerations

The Taxanes: Dosing and Scheduling Considerations

ABSTRACT: Optimal dosing and scheduling are among the most important issues being addressed in clinical studies of the taxanes. The results to date indicate that there may not be a single administration schedule that produces optimal antitumor efficacy. Instead, the specific doses of the taxanes relative to each schedule and the overall aggressiveness of the dosing schedule should be considered. There appears to be a threshold taxane dose or concentration below which only negligible antitumor activity is observed, as well as a plateau dose or concentration above which no further antitumor activity occurs. The doses at which both threshold effects and plateauing of dose-response curves occur seem to be inversely proportional to the duration of the administration schedule. For paclitaxel (Taxol), it appears that comparable antitumor effects are achieved with both short (1- and 3-hour) and prolonged (24- and 96-hour) schedules as long as equitoxic dosing regimens are used. The majority of clinical studies with docetaxel have used a somewhat aggressive dosing schedule, 100 mg/m² over 1 hour, which marks the outer edge of the dosing envelope, but nonrandomized trial results suggest a dose-response relationship in the 60- to 100-mg/m² dosing range. [ONCOLOGY 11(Suppl):7-19, 1997]

Introduction

The determination of optimal dosing and scheduling has been an important
objective during the development of the taxanes. This issue pertains to
both paclitaxel (Taxol) and docetaxel (Taxotere). The clinical development
of docetaxel has largely involved a single administration schedule (1-hour
infusion) and a narrow dosing range (60 to 100 mg/m², with most studies
using 100 mg/m² over 1 hour every 3 weeks). The range of paclitaxel
doses and schedules, on the other hand, has been broad (ranging from 135
to 250 mg/m² over 1 to 96 hours every 3 weeks).

Impressive antitumor activity has been reported recently for paclitaxel
on disparate administration schedules, which leads to the question of whether
an optimal dosing schedule truly exists for the taxanes. Fortunately, the
results of several prospective randomized studies, in addition to retrospective
analyses, may shed light on these questions. This review summarizes pertinent
preclinical, pharmacologic, and antitumor results pertaining to optimal
taxane dosing and scheduling in clinical practice.

In Vitro Cytotoxicity Studies

The results of in vitro studies designed to evaluate taxane dose-response
relationships and optimal taxane scheduling have been reviewed previously.[1,2]
Many relevant biologic effects in vitro, such as cytotoxicity, formation
of microtubule bundles and mitotic asters, increase in tubulin polymer
mass, stabilization of microtubules against depolymerization, apoptosis,
radiosensitization, antiangiogenesis, and inhibition of chemotaxis and
motility, appear to be directly related to the concentration of the taxanes.[3-14]

The taxanes may induce different intracellular effects, depending on
the drug concentration. They inhibit proliferation of cells by inducing
a sustained mitotic block at the metaphase/anaphase boundary at concentrations
much lower than those required to increase microtubule mass and microtubule
bundle formation.[15] Half-maximal inhibition of HeLa cell proliferation
and 50% blockade of mitotic metaphase occur at 8 nM of paclitaxel, whereas
microtubule mass increases half-maximally at 80 nM of paclitaxel, with
maximal effect at 300 nM.[15] At high concentrations, the unique effects
of paclitaxel in increasing microtubule mass and microtubule bundles have
been associated with growth inhibition.[12,15]

Because these effects have not been noted at the lowest effective concentrations,
they could not have accounted for the antiproliferative effects observed
at low concentrations. Instead, growth inhibition has been associated with
the formation of an incomplete metaphase plate of chromosomes and an arrangement
of spindle microtubules resembling the abnormal organization that occurs
at low concentrations of the Vinca alkaloids.[16]

Plateau and Threshold Concentrations

As paclitaxel concentrations progressively increase, a plateauing of
dose-response effects has been observed in various cell lines.[12,17-22]
In other words, a situation of diminishing returns occurs as paclitaxel
and docetaxel concentrations are increased above specific plateau concentrations,
the magnitude of which appears to vary between cell lines. The broad clinical
implication of these results is that there may be a critical plateau concentration,
ie, a dose above which toxicity, but not efficacy, increases.

The cumulative results of in vitro studies suggest that the precise
concentrations at which plateauing occurs depends on the specific treatment
schedule and varies according to tumor type. In addition, there appear
to be precise threshold concentrations below which drug effects do not
usually occur. Like plateau concentrations, the precise level at which
threshold effects take place also varies among cell lines. Threshold concentrations
typically are inversely related to the duration of treatment. In essence,
these preclinical observations resemble clinical observations to date.

Treatment Duration

For both paclitaxel and docetaxel, treatment duration appears to be
the most critical determinant of in vitro effect. Prolonging the duration
of exposure in vitro generally produces much greater cytotoxicity than
increasing drug concentration.[1,2,9,12,14,17,18, 20,23-25] For example,
an 11-fold increase in the duration of paclitaxel exposure was more effective
in increasing the cytotoxic effect of paclitaxel in an LC8A lymphoma cell
line than was a 100-fold increase in paclitaxel concentration.[12] Interestingly,
this effect appears to be much more pronounced in taxane-resistant cell
lines.[24,26-29] The taxane concentrations at which cell survival curves
plateau tend to decrease as the treatment durations are prolonged.

For paclitaxel, and probably docetaxel, the effects of increasing microtubule
mass are maximal at drug concentrations that are equimolar with tubulin
or when the stoichiometry approaches 1 M of paclitaxel per 1 M of polymerized
tubulin dimer.[4,30-33] The binding of paclitaxel to polymerized tubulin
is reversible with a binding constant of approximately 0.9 µM. Docetaxel,
which most likely shares the same tubulin binding site as paclitaxel, has
a 1.9-fold higher effective affinity for the site.[4] The assembly of guanosine
diphosphate- or guanosine triphosphate-tubulin induced by docetaxel also
proceeds with a critical protein concentration that is 2.1-fold lower than
that of paclitaxel.[4] In addition, comparative in vitro cellular pharmacologic
studies have demonstrated that higher intracellular levels of docetaxel
in P388 murine leukemia cells may also be attributed, in part, to its threefold
slower efflux rate.[4]

These differences may explain the varying cytotoxic potencies of the
taxanes, with median inhibitory concentrations generally much lower for
docetaxel.[4,21,22,33-36] The relative potencies may not necessarily translate
into a greater therapeutic index for docetaxel, since greater potency may
also result in more severe toxicity at identical drug concentrations in
vitro. In addition, the taxanes may
not be completely cross-resistant, although differences in potency may
confound the interpretation of both preclinical and clinical studies regarding
cross-resistance.

These schedule-dependent effects have also been documented in studies
designed to determine the
in vitro interactions of the taxanes with ionizing radiation.[9] In most
studies, the radiopotentiating effects of the taxanes have been directly
related to the duration of taxane exposure prior to radiation.[9] In one
series of studies involving lung cancer cells, a radiosensitizing effect
could not be demonstrated for treatment durations of less than 6 hours
at any concentration of paclitaxel.[37]

Preclinical Studies

In early studies performed by the National Cancer Institute, paclitaxel
was administered as a suspension and antitumor evaluations were limited
to studies using intraperitoneally (IP) implanted tumors treated with IP
drug administration or human tumor xenografts implanted in the subrenal
capsule and treated subcutaneously.[38] In mice-bearing IP-implanted P388
leukemia, paclitaxel administered every 3 hours for three doses (pharmacologically
simulating a 24-hour infusion schedule) was more effective than other schedules,
including those with multiple-drug treatments on days 1, 5, and 9, or daily
treatment for 9 consecutive days.[38] However, these studies were constrained
due to the limited solubility of paclitaxel in the formulation vehicles
used at that time, thereby precluding the design of proper comparative
studies of prolonged schedules and single-dosing schedules.

Lung Cancer Model

When studies designed to evaluate different schedules were later performed
by Bristol-Myers Squibb in the M109 lung cancer model using polyoxyethylated
castor oil (Cremophor EL) or polysorbate 80 formulations, no schedule-dependent
differences were observed.[39] However, neither the optimal schedule demonstrated
in the P388 leukemia studies (every 3 hours × 8 doses) nor prolonged
(eg, 3 24-hour) infusion schedules were evaluated.

The schedule-finding studies in the M109 model indicated that both daily
× 5 and daily × 7 schedules were superior to multiple daily
dosing for longer intervals (2 or 3 days between injections). Significantly,
maximal antitumor activity was achieved at doses that were substantially
lower than the maximum tolerated dose (MTD). This was particularly true
for the daily × 7-day schedule, in which dosing at the MTD did not
result in any therapeutic advantage over an equally effective, but less
toxic, lower dose.[40] These results are consistent with the plateau effects
noted in the dose-response curves from a variety of cell lines.

Other Models

Nevertheless, dose-response effects have been observed in many other
preclinical in vitro models. Progressive reductions in vertebral metastases
were noted in combined immunodeficient mice inoculated with PC-3 ML prostate
cancer cells that were previously incubated with increasing paclitaxel
concentrations from 0.1 to 1.0 µM [41] and in mice bearing bladder
cancer.[42]

Dose-toxicity relationships have been especially profound. Substantially
greater toxicity in both rapidly proliferating (lymphoid, myeloid, gastrointestinal)
and nonproliferating (peripheral nerve) tissues has been observed on almost
all schedules in mice, rats, and dogs.[43-45] The schedule's effects are
more profound in that lower total doses are typically required to induce
equivalent toxic effects in animals treated with more intermittent dosing
schedules or treatment over more prolonged durations.[38,43]

It is difficult to compare paclitaxel and docetaxel with respect to
dose and schedule dependency in preclinical studies in animals due to differences
in tumor models, dosing schedules, and the proximity of treatment doses
to the MTD. Nevertheless, results of limited studies with docetaxel have
indicated clear dose-response relationships, particularly with short- and
single-dosing schedules. Although one may conclude that the type of administration
schedule appears to have minimal impact on docetaxel's antitumor activity,
it should be noted that only limited studies with prolonged schedules have
been performed.[5,46,47]